Synthetic transtaganolide and basiliolide products, derivatives thereof, and synthesis methods thereof

ABSTRACT

Compounds represented by Formula I are provided that include synthetic transtaganolide and basiliolide products. Derivatives of these compounds and methods of synthesis are also provided.

CROSS-REFERENCE TO RELATED APPLICATION(S)

The present application claims priority to and the benefit of U.S.Provisional Application Ser. No. 61/433,844 filed on Jan. 18, 2011, theentire contents of which are incorporated herein by reference.

BACKGROUND

The transtaganolides and basiliolides compounds 1-3 as shown in Diagram1, are members of a growing family of natural products isolated fromplants belonging to the genus Thapsia. Compounds within this group(e.g., compounds 1a, 1b, and 3a) have been shown to induce rapidmobilization of intracellular Ca²⁺ stores. This activity has beenattributed to the inhibition of calcium ATPases residing within thesarco/endoplasmic reticulum (SERCA-ATPases). Thapsia sp. are also theplan source of the commonly employed and structurally unrelatedSERCA-ATPase inhibitor, thapsigargin (compound 4). Furthermore, Oikawaand coworkers have proposed a structure-function relationship to thewidely utilized anti-malarial agent artemisinin (compound 5), which hasalso been proposed to act via ATPase inhibition. Other reports suggest amode of action independent of ATPase inhibition.

Structurally, the transtaganolide/basiliolide molecules possess a densearray of functionalization and a polycyclic ring system comprised oftrans-decalin framework, a bridging lactone (see 1a rings A and B) andan unprecedented cyclic acyl ketene acetal (ring C).

Owing to the interesting biological activity and striking architectures,the transtaganolides (compounds 1 and 2) and basiliolides (compound 3)have inspired significant interest from the synthetic community. Despitethese early developments by multiple research groups and the disclosureof these advanced intermediates, total synthesis of transtaganolides orbasiliolides has not been reported.

SUMMARY

In some embodiments of the preset invention, a synthetic compound isprovided represented by Formula I:

-   wherein:-   Y is selected from —OR⁹, —N, R¹⁰, R¹¹, —SR¹², wherein R⁹, R¹⁰, R¹¹,    and R¹² are each independently selected from hydrocarbyl,    substituted hydrocarbyl, heteroatom-containing hydrocarbyl, or    substituted heteroatom-containing hydrocarbyl;-   W is selected from —O, —S, or —NR²¹, wherein R²¹ is hydrogen,    hydrocarbyl, substituted hydrocarbyl, heteroatom-containing    hydrocarbyl, or substituted heteroatom-containing hydrocarbyl;-   Z is selected from —O, —S, or —NR²², wherein R²² is hydrogen,    hydrocarbyl, substituted hydrocarbyl, heteroatom-containing    hydrocarbyl, or substituted heteroatom-containing hydrocarbyl;-   R¹, R², and R³ are each independently selected from hydrogen,    hydrocarbyl, substituted hydrocarbyl, heteroatom-containing    hydrocarbyl, substituted heteroatom-containing hydrocarbyl;-   R⁴, R⁵, and R⁶ are independently selected from hydrogen,    hydrocarbyl, substituted hydrocarbyl, heteroatom-containing    hydrocarbyl, or substituted heteroatom-containing hydrocarbyl; and-   R⁷ and R⁸ are independently selected from hydrogen, hydrocarbyl,    substituted hydrocarbyl, heteroatom-containing hydrocarbyl, or    substituted heteroatom-containing hydrocarbyl; and-   any two or more adjacent R groups optionally combine to form a ring.

Some embodiments of the present invention are directed to a method ofenriching for an enantiomer of Formula I, including synthesizing acompound of Formula III in which one of R^(7′) and R^(8′) is a silylgroup and the other of R^(7′) and R^(8′) is hydrogen, including removingthe silyl group to form an enantioselective compound; and reacting acompound of Formula II with the enantioselective Formula III compound,to form the compound of Formula I,

-   wherein:-   Y is selected from —OR⁹, —N, R¹⁰, R¹¹, —SR¹², wherein R⁹, R¹⁰, R¹¹,    and R¹² are each independently selected from hydrocarbyl,    substituted hydrocarbyl, heteroatom-containing hydrocarbyl, or    substituted heteroatom-containing hydrocarbyl;-   M is selected from Li, Na, hydrogen, SiR¹³R¹⁴R¹⁵, SnR¹⁶R¹⁷R¹⁸,    BR¹⁹R²⁰, and ZnX₂ wherein R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, and R¹⁸ are each    independently selected from hydrocarbyl or substituted hydrocarbyl,    R¹⁹ and R²⁰ are each independently selected from hydrocarbyl,    substituted hydrocarbyl, heteroatom-containing hydrocarbyl, or    substituted heteroatom-containing hydrocarbyl, and X is any halogen;-   W is selected from —O, —S, or —NR²¹, wherein R²¹ is hydrogen,    hydrocarbyl, substituted hydrocarbyl, heteroatom-containing    hydrocarbyl, or substituted heteroatom-containing hydrocarbyl;-   Z is selected from —O, —S, or —NR²², wherein R²² is hydrogen,    hydrocarbyl, substituted hydrocarbyl, heteroatom-containing    hydrocarbyl, or substituted heteroatom-containing hydrocarbyl;-   R¹, R², and R³ are each independently selected from hydrogen,    hydrocarbyl, substituted hydrocarbyl, heteroatom-containing    hydrocarbyl, or substituted heteroatom-containing hydrocarbyl; and-   R⁴, R⁵, and R⁶ are each independently selected from hydrogen,    hydrocarbyl, substituted hydrocarbyl, heteroatom-containing    hydrocarbyl, or substituted heteroatom-containing hydrocarbyl; and-   any two or more adjacent R groups optionally combine to form a ring.

In other embodiments of the present invention, a compound, including asynthetic compound represented by Formula IV is provided:

wherein:

-   R_(a) is selected from hydrocarbyl, substituted hydrocarbyl,    heteroatom-containing hydrocarbyl, or substituted    heteroatom-containing hydrocarbyl;-   W_(a) is selected from —OR^(X), —SR^(XX), and —NR^(XXX)R^(XXXX),    where each of R^(X), R^(XX), R^(XXX) and R^(XXXX) is independently    selected from hydrogen, hydrocarbyl, substituted hydrocarbyl,    heteroatom-containing hydrocarbyl, or substituted    heteroatom-containing hydrocarbyl;-   each of R³ through R⁸ is selected from hydrogen, hydrocarbyl,    substituted hydrocarbyl, heteroatom-containing hydrocarbyl, or    substituted heteroatom-containing hydrocarbyl;-   Z is selected from —O, —S and —NR²², wherein R²² is selected from    hydrocarbyl, substituted hydrocarbyl, heteroatom-containing    hydrocarbyl, or substituted heteroatom-containing hydrocarbyl; and-   any two or more of R_(a) and R³ through R⁸ optionally combine to    form a ring.

In other embodiments of the present invention, a method of synthesizinga compound of Formula IV, includes reacting a compound of Formula IV-Iwith a compound of Formula IV-II according to reaction scheme 11 to formthe compound of Formula IV:

wherein:

-   R_(a) is selected from hydrocarbyl, substituted hydrocarbyl,    heteroatom-containing hydrocarbyl, or substituted    heteroatom-containing hydrocarbyl;-   W_(a) is selected from —OR^(X), —SR^(XX), and —NR^(XXX)R^(XXXX),    where each of R^(X), R^(XX), R^(XXX) and R^(XXXX) is independently    selected from hydrogen, hydrocarbyl, substituted hydrocarbyl,    heteroatom-containing hydrocarbyl, or substituted    heteroatom-containing hydrocarbyl;-   each of R³ through R⁸ is selected from hydrogen, hydrocarbyl,    substituted hydrocarbyl, heteroatom-containing hydrocarbyl, or    substituted heteroatom-containing hydrocarbyl;-   Z is selected from the group consisting of —O, —S and —NR²², wherein    R²² is selected from hydrocarbyl, substituted hydrocarbyl,    heteroatom-containing hydrocarbyl, or substituted    heteroatom-containing hydrocarbyl;-   M is selected from Li, Na, hydrogen, SiR¹²R¹⁴R¹⁵, SnR¹⁶R¹⁷R¹⁸,    BR¹⁹R²⁰, MgX′₂ and ZnX″₂, where:    -   each of R¹³ through R¹⁸ is independently selected from        hydrocarbyl or substituted hydrocarbyl,    -   each of R¹⁹ and R²⁰ is independently selected from hydrogen,        hydrocarbyl, substituted hydrocarbyl, heteroatom-containing        hydrocarbyl, or substituted heteroatom-containing hydrocarbyl,        and    -   each of X′ and X″ is independently selected from halogens; X is        a halogen; and any two or more of R_(a) and R³ through R⁸        optionally combined to form a ring.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a ¹H NMR spectrum of transtaganolide C (1a), according toaspects of the present invention.

FIG. 2 is a ¹³C NMR spectrum of transtaganolide C (1a), according toaspects of the present invention.

FIG. 3 is a ¹H NMR spectrum of transtaganolide D (1b), according toaspects of the present invention.

FIG. 4 is a ¹³C NMR spectrum of transtaganolide D (1b), according toaspects of the present invention.

FIG. 5 is a ¹H NMR spectrum of basiliolide B (3a), according to aspectsof the present invention.

FIG. 6 is a ¹³C NMR spectrum of basiliolide B (3a), according to aspectsof the present invention.

FIG. 7 is a ¹H NMR spectrum of tert-butyldimethylsilyl ester (6b),according to aspects of the present invention.

FIG. 8 is a ¹³C NMR spectrum of tert-butyldimethylsilyl ester (6b),according to aspects of the present invention.

FIG. 9 is a ¹H NMR spectrum of ester (7b), according to aspects of thepresent invention.

FIG. 10 is a ¹H NMR spectrum of iodoacid (6c), according to aspects ofthe present invention.

FIG. 11 is a ¹³C NMR spectrum of iodoacid (6c), according to aspects ofthe present invention.

FIG. 12 is a ¹H NMR spectrum of tert-butyldimethylsilyl ester (6d),according to aspects of the present invention.

FIG. 13 is a ¹³C NMR spectrum of tert-butyldimethylsilyl ester (6d),according to aspects of the present invention.

FIG. 14 is a ¹H NMR spectrum of trimethylsilyl pyrone ester, accordingto aspects of the present invention.

FIG. 15 is a ¹H NMR spectrum of trimethylsilyl iodoacid, according toaspects of the present invention.

FIG. 16 is a ¹H NMR spectrum of a representative example of a compoundof Formula IV, in which R_(a) is a vinyl moiety and W_(a) is methoxy,according to aspects of the present invention.

FIG. 17 is a ¹H NMR spectrum of a representative example of a compoundof Formula IV, in which R_(a) is an ethoxyacetylene moiety and W_(a) ismethoxy, according to aspects of the present invention.

DETAILED DESCRIPTION

It is to be understood that unless otherwise indicated this invention isnot limited to specific reactants, reaction conditions, ligands, metalcomplexes, or the like, as such may vary. It is also to be understoodthat the terminology used herein is for the purpose of describingparticular embodiments only and is not intended to be limiting.

Where lists are used to identify multiple embodiments, it is understoodthat modifiers stated at the beginning of the list apply to each elementin the list. Thus, for example, in a list of “chiral compounds”, eachcompound in the list is understood to be chiral.

As used in the specification and the appended claims, the singular forms“a,” “an” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “a compound”encompasses a combination or mixture of different compounds as well as asingle compound, reference to “a functional group” includes a singlefunctional group as well as two or more functional groups that may ormay not be the same, and the like.

In this specification and in the claims that follow, reference will bemade to a number of terms, which shall be defined to have the followingmeanings:

As used herein, the phrase “having the formula” or “having thestructure” is not intended to be limiting and is used in the same waythat the term “comprising” is commonly used.

The term “alkyl” as used herein refers to a linear, branched or cyclicsaturated hydrocarbon group typically although not necessarilycontaining 1 to about 24 carbon atoms, such as methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, t-butyl, octyl, decyl, and the like, aswell as cycloalkyl groups such as cyclopentyl, cyclohexyl and the like.Generally, although again not necessarily, alkyl groups herein contain 1to about 12 carbon atoms. The term “lower alkyl” intends an alkyl groupof 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, and the specificterm “cycloalkyl” intends a cyclic alkyl group, typically having 4 to 8,preferably 5 to 7, carbon atoms. The term “substituted alkyl” refers toalkyl substituted with one or more substituent groups, and the terms“heteroatom-containing alkyl” and “heteroalkyl” refer to alkyl in whichat least one carbon atom is replaced with a heteroatom. If not otherwiseindicated, the terms “alkyl” and “lower alkyl” include linear, branched,cyclic, unsubstituted, substituted, and/or heteroatom-containing alkyland lower alkyl, respectively.

The term “alkenyl” as used herein refers to a linear, branched or cyclichydrocarbon group of 2 to 24 carbon atoms containing at least one doublebond, such as ethenyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl,octenyl, decenyl, tetradecenyl, hexadecenyl, eicosenyl, tetracosenyl,and the like. Preferred alkenyl groups herein contain 2 to 12 carbonatoms. The term “lower alkenyl” intends an alkenyl group of 2 to 6carbon atoms, preferably 2 to 4 carbon atoms, and the specific term“cycloalkenyl” intends a cyclic alkenyl group, preferably having 5 to 8carbon atoms. The term “substituted alkenyl” refers to alkenylsubstituted with one or more substituent groups, and the terms“heteroatom-containing alkenyl” and “heteroalkenyl” refer to alkenyl inwhich at least one carbon atom is replaced with a heteroatom. If nototherwise indicated, the terms “alkenyl” and “lower alkenyl” includelinear, branched, cyclic, unsubstituted, substituted, and/orheteroatom-containing alkenyl and lower alkenyl, respectively.

The term “alkynyl” as used herein refers to a linear or branchedhydrocarbon group of 2 to 24 carbon atoms containing at least one triplebond, such as ethynyl, n-propynyl, and the like. Preferred alkynylgroups herein contain 2 to 12 carbon atoms. The term “lower alkynyl”intends an alkynyl group of 2 to 6 carbon atoms, preferably 2 to 4carbon atoms. The term “substituted alkynyl” refers to alkynylsubstituted with one or more substituent groups, and the terms“heteroatom-containing alkynyl” and “heteroalkynyl” refer to alkynyl inwhich at least one carbon atom is replaced with a heteroatom. If nototherwise indicated, the terms “alkynyl” and “lower alkynyl” includelinear, branched, unsubstituted, substituted, and/orheteroatom-containing alkynyl and lower alkynyl, respectively.

The term “alkoxy” as used herein intends an alkyl group bound through asingle, terminal ether linkage; that is, an “alkoxy” group may berepresented as —O-alkyl where alkyl is as defined above. A “loweralkoxy” group intends an alkoxy group containing 1 to 6 carbon atoms,preferably 1 to 4 carbon atoms. Analogously, “alkenyloxy” and “loweralkenyloxy” respectively refer to an alkenyl and lower alkenyl groupbound through a single, terminal ether linkage, and “alkynyloxy” and“lower alkynyloxy” respectively refer to an alkynyl and lower alkynylgroup bound through a single, terminal ether linkage.

The term “aryl” as used herein, and unless otherwise specified, refersto an aromatic substituent containing a single aromatic ring or multiplearomatic rings that are fused together, directly linked, or indirectlylinked (such that the different aromatic rings are bound to a commongroup such as a methylene or ethylene moiety). Preferred aryl groupscontain 5 to 24 carbon atoms, and particularly preferred aryl groupscontain 5 to 14 carbon atoms. Exemplary aryl groups contain one aromaticring or two fused or linked aromatic rings, e.g., phenyl, naphthyl,biphenyl, diphenylether, diphenylamine, benzophenone, and the like.“Substituted aryl” refers to an aryl moiety substituted with one or moresubstituent groups, and the terms “heteroatom-containing aryl” and“heteroaryl” refer to aryl substituent, in which at least one carbonatom is replaced with a heteroatom, as will be described in furtherdetail infra.

The term “aryloxy” as used herein refers to an aryl group bound througha single, terminal ether linkage, wherein “aryl” is as defined above. An“aryloxy” group may be represented as —O-aryl where aryl is as definedabove. Preferred aryloxy groups contain 5 to 24 carbon atoms, andparticularly preferred aryloxy groups contain 5 to 14 carbon atoms.Examples of aryloxy groups include, without limitation, phenoxy,o-halo-phenoxy, m-halo-phenoxy, p-halo-phenoxy, o-methoxy-phenoxy,m-methoxy-phenoxy, p-methoxy-phenoxy, 2,4-dimethoxy-phenoxy,3,4,5-trimethoxy-phenoxy, and the like.

The term “alkaryl” refers to an aryl group with an alkyl substituent,and the term “aralkyl” refers to an alkyl group with an arylsubstituent, wherein “aryl” and “alkyl” are as defined above. Preferredalkaryl and aralkyl groups contain 6 to 24 carbon atoms, andparticularly preferred alkaryl and aralkyl groups contain 6 to 16 carbonatoms. Alkaryl groups include, for example, p-methylphenyl,2,4-dimethylphenyl, p-cyclohexylphenyl, 2,7-dimethylnaphthyl,7-cyclooctylnaphthyl, 3-ethyl-cyclopenta-1,4-diene, and the like.Examples of aralkyl groups include, without limitation, benzyl,2-phenyl-ethyl, 3-phenyl-propyl, 4-phenyl-butyl, 5-phenyl-pentyl,4-phenylcyclohexyl, 4-benzylcyclohexyl, 4-phenylcyclohexylmethyl,4-benzylcyclohexylmethyl, and the like. The terms “alkaryloxy” and“aralkyloxy” refer to substituents of the formula —OR wherein R isalkaryl or aralkyl, respectively, as just defined.

The term “acyl” refers to substituents having the formula —(CO)-alkyl,—(CO)-aryl, or —(CO)-aralkyl, and the term “acyloxy” refers tosubstituents having the formula —O(CO)-alkyl,

—O(CO)-aryl, or —O(CO)-aralkyl, wherein “alkyl,” “aryl, and “aralkyl”are as defined above.

The term “cyclic”, “cycle”, or “ring” refers to alicyclic or aromaticsubstituents that may or may not be substituted and/or heteroatomcontaining, and that may be monocyclic, bicyclic, or polycyclic. Theterm “alicyclic” is used in the conventional sense to refer to analiphatic cyclic moiety, as opposed to an aromatic cyclic moiety, andmay be monocyclic, bicyclic or polycyclic.

The terms “halo” and “halogen” are used in the convention sense to referto a chloro, bromo, fluoro or iodo substituent.

“Hydrocarbyl” refers to univalent hydrocarbyl radicals containing 1 toabout 30 carbon atoms, preferably 1 to about 24 carbon atoms, mostpreferably 1 to about 12 carbon atoms, including linear, branched,cyclic, saturated and unsaturated species, such as alkyl groups, alkenylgroups, aryl groups, and the like. The term “lower hydrocarbyl” intendsa hydrocarbyl group of 1 to 6 carbon atoms, preferably 1 to 4 carbonatoms, and the term “hydrocarbylene” intends a divalent hydrocarbylmoiety containing 1 to about 30 carbon atoms, preferably 1 to about 23carbon atoms, most preferably 1 to about 12 carbon atoms, includinglinear, branched, cyclic, saturated and unsaturated species. The term“lower hydrocarbylene” intends a hydrocarbylene group of 1 to 6 carbonatoms. “Substituted hydrocarbyl” refers to hydrocarbyl substituted withone or more substituent groups, and the terms “heteroatom-containinghydrocarbyl” and “heterohydrocarbyl” refer to hydrocarbyl in which atleast one carbon atom is replaced with a heteroatom. Similarly,“substituted hydrocarbylene” refers to hydrocarbylene substituted withone or more substituent groups, and the terms “heteroatom-containinghydrocarbylene” and heterohydrocarbylene” refer to hydrocarbylene inwhich at least one carbon atom is replaced with a heteroatom. Unlessotherwise indicated, the term “hydrocarbyl” and “hydrocarbylene” are tobe interpreted as including substituted and/or heteroatom-containinghydrocarbyl and hydrocarbylene moieties, respectively.

The term “heteroatom-containing” as in a “heteroatom-containinghydrocarbyl group” refers to a hydrocarbon molecule or a hydrocarbylmolecular fragment in which one or more carbon atoms is replaced with anatom other than carbon, e.g., nitrogen, oxygen, sulfur, phosphorus orsilicon, typically nitrogen, oxygen or sulfur. Similarly, the term“heteroalkyl” refers to an alkyl substituent that isheteroatom-containing, the term “heterocyclic” refers to a cyclicsubstituent that is heteroatom-containing, the terms “heteroaryl” andheteroaromatic” respectively refer to “aryl” and “aromatic” substituentsthat are heteroatom-containing, and the like. It should be noted that a“heterocyclic” group or compound may or may not be aromatic, and furtherthat “heterocycles” may be monocyclic, bicyclic, or polycyclic asdescribed above with respect to the term “aryl.”

By “substituted” as in “substituted alkyl,” “substituted aryl,” and thelike, as alluded to in some of the aforementioned definitions, is meantthat in the alkyl, aryl, or other moiety, at least one hydrogen atombound to a carbon (or other) atom is replaced with one or morenon-hydrogen substituents. Examples of such substituents include,without limitation: functional groups such as halo, hydroxyl,sulfhydryl, C₁-C₂₄ alkoxy, C₂-C₂₄alkenyloxy, C₂-C₂₄ alkynyloxy, C₅-C₂₄aryloxy, acyl (including C₂-C₂₄ alkylcarbonyl (—CO-alkyl) and C₆-C₂₄arylcarbonyl (—CO-aryl)), acyloxy (—O-acyl), C₂-C₂₄ alkoxycarbonyl(—(CO)—O-alkyl), C₆-C₂₄ aryloxycarbonyl (—(CO)—O-aryl), halocarbonyl(—CO)—X where X is halo), C₂-C₂₄ alkylcarbonato (—O—(CO)—O-alkyl),C₆-C₂₄ arylcarbonato (—O—(CO)—O-aryl), carboxy (—COOH), carboxylato(—COO⁻), carbamoyl (—(CO)—NH₂), mono-(C₁-C₂₄ alkyl)-substitutedcarbamoyl (—(CO)—NH(C₁-C₂₄ alkyl)), di-(C₁-C₂₄ alkyl)-substitutedcarbamoyl (—(CO)—N(C₁-C₂₄ alkyl)₂), mono-(C₆-C₂₄ aryl)-substitutedcarbamoyl (—(CO)—NH-aryl), di-(C₆-C₂₄ aryl)-substituted carbamoyl(—(CO)—N(aryl)₂), d-N-(C₁-C₂₄ alkyl), N-(C₆-C₂₄ aryl)-substitutedcarbamoyl, thiocarbamoyl (—(CS)—NH₂), carbamido (—NH—(CO)—NH₂), cyano(—C≡N), isocyano (—N⁺≡C⁻), cyanato (—O—C≡N), isocyanato (—O—N⁺≡C⁻),isothiocyanato (—S—C≡N), azido (—N═N⁺N═N⁻), formyl (—(CO)—H), thioformyl(—(CS)—H), amino (—NH₂), mono-(C₁-C₂₄ alkyl)-substituted amino,di-(C₁-C₂₄ alkyl)-substituted amino, mono-(C₅-C₂₄ aryl)-substitutedamino, di-(C₅-C₂₄ aryl)-substituted amino, C₂-C₂₄ alkylamido(—NH—(CO)-alkyl), C₆-C₂₄ arylamido (—NH—(CO)-aryl), imino (—CR═NH whereR=hydrogen, C₁-C₂₄ alkyl, C₅-C₂₄ aryl, C₆-C₂₄ alkaryl, C₆-C₂₄ aralkyl,etc.), alkylimino (—CR═N (alkyl), where R=hydrogen, C₁-C₂₄ alkyl, C₅-C₂₄aryl, C₆-C₂₄ alkaryl, C₆-C₂₄ aralkyl, etc.), arylimino (—CR═N (aryl),where R=hydrogen, C₁-C₁-C₂₄ alkyl, C₅-C₂₄ aryl, C₆-C₂₄ alkaryl, C₆-C₂₄aralkyl, etc.), nitro (—NO₂), nitroso (—NO), sulfo (—SO₂—OH), sulfonato(—SO₂—O⁻), C₁-C₂₄ alkylsulfanyl (—S-alkyl; also termed “alkylthio”),arylsulfanyl (—S-aryl; also termed “arylthio”), C₁-C₂₄ alkylsulfinyl(—(SO)-alkyl), C₅-C₂₄ arylsulfinyl (—(SO)-aryl), C₁-C₂₄ alkylsulfonyl(—SO₂-alkyl), C₅-C₂₄ arylsulfonyl (—SO₂-aryl), boryl (—BH₂), borono(—B(OH)₂), boronato (—B(OR)₂ where R is alkyl or other hydrocarbyl),phosphono (—P(O)(OH)₂), phosphonato (—P(O)(O⁻)₂), phosphinato(—P(O)(O⁻)), phospho (—PO₂), and phosphino (—PH₂); and the hydrocarbylmoieties C₁-C₂₄ alkyl (preferably C₁-C₁₂ alkyl, more preferably C₁-C₆alkyl), C₂-C₂₄ alkenyl (preferably C₂-C₁₃ alkenyl, more preferably C₂-C₆alkenyl), C₂-C₂₄ alkynyl (preferably C₂-C₁₂ alkynyl, more preferablyC₂-C₆ alkynyl), C₅-C₂₄ aryl (preferably C₅-C₁₄ aryl), C₆-C₂₄ alkaryl(preferably C₆-C₁₆ alkaryl), and C₆-C₂₄ aralkyl (preferably C₆-C₁₆aralkyl).

In addition, the aforementioned functional groups may, if a particulargroup permits, be further substituted with one or more additionalfunctional groups or with one or more hydrocarbyl moieties such as thosespecially enumerated above. Analogously, the above-mentioned hydrocarbylmoieties may be further substituted with one or more functional groupsor additional hydrocarbyl moieties such as those specially enumerated.

When the term “substituted” appears prior to a list of possiblesubstituted groups, it is intended that the term apply to every memberof that group. For example, the phrase “substituted alkyl, alkenyl, andaryl” is to be interpreted as “substituted alkyl, substituted alkenyl,and substituted aryl.” analogously, when the term“heteroatom-containing” appears prior to a list of possibleheteroatom-containing groups, it is intended that the term apply toevery member of that group. For example, the phrase“heteroatom-containing alkyl, alkenyl, and aryl” is to be interpreted as“heteroatom-containing alkyl, substituted alkenyl, and substitutedaryl.”

“Optional” or “optionally” means that the subsequently describedcircumstance may or may not occur, so that the description includesinstances where the circumstance occurs and instances, where it doesnot. For example, the phrase “optionally substituted” means that anon-hydrogen substituent may or may not be present on a given atom, and,thus, the description includes structures wherein a non-hydrogensubstituent is present and structures wherein a non-hydrogen substituentis not present.

In the molecular structures herein, the use of bold and dashed lines todenote particular conformation of groups follows the IUPAC convention. Abond indicated by a broken line indicates that the group in question isbelow the general plane of the molecule as drawn (the “α”configuration), and a bond indicated by a bold line indicates that thegroup at the position in question is above the general plane of themolecule as drawn (the “β” configuration).

The terms “enantiomer excess,” “enantiomeric excess,” and “e.e.” areused interchangeably and are defined as |F(+)−F(−)| for a mixture of(+)- and (−)-enantiomers, with composition given as the mole or weightfractions F(+) and F(−), such that F(+)+F(−)=1. When given as apercentage, enantiomer excess is defined by 100*|F(+)−F(−)|.“Enantioselective” is used to refer to a reactant that can enrich forone enantiomer. “Enantioenriched” refers the enriched product(s) havingan increase of, or more of, one enantiomer compound.

The terms “racemate,” “racemic form,” and “racemic mixture” are usedinterchangeably to refer to a substantially equimolar mixture of twoenantiomers, and can be designated using the (±) symbol.

A person of ordinary skill in the art recognizes that the temperaturefor a reaction can vary widely, producing the same reaction product,albeit at varying lengths of time. In general the compounds used hereinare not stable above 120° C. Accordingly, all reactions disclosed hereinfor the disclosed compounds may be performed from 0 to 120° C. dependingon the stability of the reagents (e.g. catalysts and solvents).

Initial efforts to synthesize basiliolides and transtaganolides utilizedan intramolecular pyrone Diels-Alder cycloaddition to construct theoxabicyclo[2.2.2]octene moiety constituting the ABD ring system ofcompound 1 (transtaganolide C, D) and compound 3 (basiliolide B) asshown in Diagram 1, below (H. M. Nelson et. al, Org. Lett. 2008, 10,25-28, M. V. Kozytska et al., Tetrahedron Lett. 2008, 49, 2899-2901; M.V. Kozytska et al., Abstracts of Papers, 234th National Meeting of theAmerican Chemical Society, Boston, Mass., Aug. 19-23, 2007; AmericanChemical Society; Washington, D.C., 2007; ORGN 1012; M. V. Kozytska etal., Abstracts of Papers, 58th Southeast Regional Meeting of theAmerican Chemical Society, Augusta, Ga., Nov. 1-4, 2006; AmericanChemical Society; Washington, D.C., 2006; SRM06 011; M. V. Kozytska, I.Siletanylmethyllithium, an ambiphilic siletane II. Synthetic approach tobasiliolide B. PhD Thesis, Florida State University College of Arts andSciences: 2008; and X. Zhou et al., Org. Lett. 2008, 10, 5525-5528, theentire contents of all of which are incorporated herein by reference.)

Furthermore, H. M. Nelson, 2009, infra and R. Larsson et al., 2009,infra, have independently demonstrated a rapid and diastereoselectiveconstruction of the tricyclic core from a simple ester precursor viasequential Ireland-Claisen rearrangement/—intramolecular pyroneDiels-Alder cycloaddition (Scheme 1), as disclosed in H. M. Nelson etal., Tetrahedron Lett. 2009, 50, 1699-1701 and R. Larsson et al., Org.Lett. 2009, 11, 657-660, the entire contents of both of which areincorporated herein by reference. This Ireland-Claisen/Diels Aldertwo-step sequence shown in Scheme 1, smoothly installs the C(8)quaternary carbon as a 2:1 mixture of diastereomers with all otherstereochemistry being controlled by the C(7) ester stereochemistry.

Despite these efforts, complete synthesis of a basiliolide ortranstaganolide compound has not yet been reported.

The challenge in advancing intermediates akin to the tricyle in compound6 (Scheme 2) to natural products of compounds 1-3 lies in the formationof the unusual 7-methoxy-4,5-dihydrooxepin-2(3H)-one ring (ring C).Embedded within this ring is an acyl ketene acetal that is potentiallylabile to both acid and base, as evidenced by the co-isolation of secoacid derivatives of compounds 1-3 from Thapsia sp. as disclosed in J. J.Rubal, et al., Phytochemistry 2007, 68, 2480-2486, the entire contentsof which are incorporated herein by reference.

In developing the methods used in the present invention, aretrosynthetic approach was considered in which the C ring may beprepared by a formal [5+2] annulation process of advanced tricyclecompound 6 and methoxyacetylene, or a suitable derivative, leadingdirectly to the natural products (Scheme 2). Continuing with theretrosynthetic approach, a method of forming the tricycle compound 6 wasinvestigated in which a tandem Claisen/Diels-Alder sequence is performedon the ester compound 7. It was found from this approach that with anavailable late stage construction of ring C, variants of this ester(e.g., compounds 7a and 7b of Scheme 2) prepared from geraniolderivatives may provide rapid, synthetic access to a number ofbasiliolide and transtaganolide products.

To build the C ring, strategies involving palladium-mediatedcross-coupling reactions were considered, and resulted in the synthesisof compounds of Formula I, including synthetic transtaganolides andbasiliolides. Accordingly, aspects of the present invention are directedto synthetic compounds represented by Formula I, and methods ofsynthesizing those compounds.

In some embodiments, a synthetic compound is represented by Formula Ibelow. In some exemplary embodiments, the synthetic compound of FormulaI substantially replicates a basiliolide or transtaganolide naturalproduct.

In some embodiments of the present invention, a synthetic compoundrepresented by Formula I is provided where Y, W, Z and R¹ through R⁸ aredefined as follows:

Y is selected from —OR⁹, —NR¹⁰R¹¹, SR¹², where R⁹, R¹⁰, R¹¹, and R¹² areindependently selected from hydrocarbyl, substituted hydrocarbyl,heteroatom-containing hydrocarbyl, or substituted heteroatom-containinghydrocarbyl, where any two adjacent R groups of R⁹, R¹⁰, R¹¹, and R¹²may optionally form a ring.

W is selected from —O, —S, or —NR²¹, where R²¹ is a hydrogen,hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl,or substituted heteroatom-containing hydrocarbyl.

Z is selected from —O, —S, or —NR²², where R²² is hydrogen, hydrocarbyl,substituted hydrocarbyl, heteroatom-containing hydrocarbyl, orsubstituted heteroatom-containing hydrocarbyl.

R¹, R², and R³ are independently selected from a hydrogen, hydrocarbyl,substituted hydrocarbyl, heteroatom-containing hydrocarbyl, orsubstituted heteroatom-containing hydrocarbyl, where any two adjacent Rgroups of R¹, R², and R³ may optionally form a ring.

R⁴, R⁵, and R⁶ are independently selected from hydrogen, hydrocarbyl,substituted hydrocarbyl, heteroatom-containing hydrocarbyl, orsubstituted heteroatom-containing hydrocarbyl, where two adjacent Rgroups of R⁴, R⁵, and R⁶ may optionally form a ring.

R⁷ and R⁸ are independently selected from hydrogen, hydrocarbyl,substituted hydrocarbyl, heteroatom-containing hydrocarbyl, orsubstituted heteroatom-containing hydrocarbyl, where two adjacent Rgroups of R⁷ and R⁸ may optionally form a ring.

In other embodiments of the present invention, a synthetic compound ofFormula I is provided, where R⁴, R⁵ and R⁶ are independently selectedfrom —OR²³, —NR²⁴R²⁵, SR²⁶, where R²³, R²⁴, R²⁵, and R²⁶ areindependently selected from hydrogen, hydrocarbyl, substitutedhydrocarbyl, heteroatom-containing hydrocarbyl, or substitutedheteroatom-containing hydrocarbyl, where any two adjacent R groups R⁴,R⁵, R⁶, R²³, R²⁴, R²⁵, and R²⁶ may optionally form a ring.

In some embodiments of the present invention, a synthetic compound ofFormula I is provided, where R⁴ is a hydrogen or methyl, R⁵ is methyl,—CH₂OAc, or —CO₂CH₃, and R⁶ is hydrogen.

In some embodiments of the present invention, a synthetic compound ofFormula I is provided, where R⁴ is —CO₂CH₃, —CH₂OAc or—C(O)N—(CH₃)(OCH₃) and R⁵ is methyl.

In other embodiments of the present invention, a synthetic compound ofFormula I is provided, where R⁷ and R⁸ are independently selected fromSiR²⁷R²⁸R²⁹, wherein R²⁷, R²⁸, and R²⁹ are independently selected fromhydrogen, hydrocarbyl, substituted hydrocarbyl, heteroatom-containinghydrocarbyl, or substituted heteroatom-containing hydrocarbyl, where twoadjacent R groups may optionally form a ring. In some embodiments, R⁷ isa hydrogen and R⁸ is SiMe₃.

In some embodiments, a synthetic composition of transtaganolide C andtranstaganolide D, includes synthetic compounds of Formula I, where Y is—OMe, W is oxygen, Z is oxygen, R¹, R², and R³ are each a hydrogen, R⁴,R⁵, and R⁶ are each methyl, and R⁷ and R⁸ are each a hydrogen.

In some embodiments of the present invention, a synthetic composition ofbasiliolide B and epi-8-basiliolide B, includes synthetic compounds ofFormula I, where Y is —OMe, W is oxygen, Z is oxygen, R¹, R², and R³ areeach hydrogen, R⁴ is methyl, R⁵ is —CO₂Me, R⁶ is methyl, and R⁷ and R⁸are each a hydrogen.

In an alternate embodiment, derivatives of Formula I are provided. Thesederivatives are useful for structure-function analysis in view of thetranstaganolide and basiliolide compounds. In some embodiments, thesederivatives are represented by a compound of Formula IV.

Formula IV is defined as follows, wherein R² through R⁸ are definedabove with respect to Formula I, and wherein R_(a) and W_(a) are definedas follows.

-   R_(a) is independently selected from a hydrocarbyl substituted    hydrocarbyl, heteroatom-containing hydrocarbyl, or substituted    heteroatom-containing hydrocarbyl, where it may optionally form a    ring with any adjacent R group. In other embodiments, R_(a) is an    alkoxy or silyl ether moiety. In other embodiments, R_(a) is vinyl    (ethylene), ethoxyacetylene, or methoxy.-   W_(a) is selected from —OR^(X), —SR^(XX), or —NR^(XXX)R^(XXXX),    where each of R^(X), R^(XX), R^(XXX), and R^(XXXX) is independently    selected from hydrogen, hydrocarbyl, substituted hydrocarbyl,    heteroatom-containing hydrocarbyl, or substituted    heteroatom-containing hydrocarbyl. In other embodiments W_(a) is    tert-butyl dimethylsilyl (TBS), tetramethylsilane (TMS), or OMe.-   Any two or more of R_(a) and R³ through R⁸ optionally combine to    form a ring.

I. Synthesis of Synthetic Compounds of Formula I

In some embodiments of the present invention, a method of synthesizing acompound of Formula I is provided. As shown below in Scheme 3, themethod includes reacting a compound of Formula II and a compound ofFormula III.

In some embodiments of the present invention, a method of synthesizing acompound of Formula I as defined above, is provided as shown in Scheme 3above, the method including reacting a compound of Formula II with acompound of Formula III, where M is selected from Li, Na, hydrogen,SiR¹³R¹⁴R¹⁵, SnR¹⁶R¹⁷R¹⁸, BR¹⁹R²⁰, ZnX₂ or MgX₂, where R¹³, R¹⁴, R¹⁵,R¹⁶, R¹⁷, and R¹⁸ are independently selected from hydrocarbyl orsubstituted hydrocarbyl; R¹⁹ and R²⁰ are independently selected fromhydrogen, hydrocarbyl, substituted hydrocarbyl, heteroatom-containinghydrocarbyl, or substituted heteroatom-containing hydrocarbyl, where twoor more adjacent R groups may optionally form a ring, and X is anyhalogen.

In some embodiments of the present invention, a compound of Formula IIand a compound of Formula III are reacted In the presence of a palladiumcatalyst (e.g., Pd(PPh₃)₄ or Pd(Pt-Bu₃)₂) in a suitable solvent, at asuitable temperature for the reagents. Examples of solvents include, butare not limited to, dimethylformamide (DMF), THF, acetonitrile,dichloromethane, dichloroethane, toluene, benzene, diethyl ether, DMSO,water, DME, DMA, cyclohexane, t-butyl methylether, carbon tetrachloride,chloroform, methanol, ethanol, heptane, pentane, hexanes, andcombinations thereof. As discussed above, temperature may vary dependingon the reagents and solvents selected.

A. Compounds of Formula III

In some embodiments of the present invention, a compound of Formula IIIis prepared by any suitable method or methods. The reagents and methodsdisclosed herein can be modified by a person having ordinary skill inthe art in view of the references incorporated herein. For example, insome embodiments, a compound of Formula III is synthesized following thereaction shown in Scheme 4 below.

Referring to Scheme 4 above, in some embodiments, a compound of FormulaIII-1 is reacted with a compound of Formula III-2 in the presence of apalladium catalyst and a solvent. In other embodiments, the palladiumcatalyst is Pd(PPh₃)₄ or Pd(Pt-Bu₃)₂). In some embodiments the reactionis carried out in the presence of triethylamine and/or copper iodide(CuI) in addition to the solvent. This reaction results in the formationof a compound of Formula III-3.

Then, the compound of Formula III-3, is reacted with Cy₂NH.HCl orCy₂NH.HBr in the presence of dichloroethane or dibromoethane. In someembodiments, the reaction occurs at 80° C. for 12 hours. This reactionresults in the formation of a compound of Formula III-4 (in which X iseither Cl or Br).

Alternatively, the compound of Formula III-3 may be reacted with I₂ orICI in a solvent. In some embodiments the solvent is a dichloromethane(DCM). In some embodiments, the reaction occurs at 25° C. for 0.5-4hours. This results in the formation of compound of Formula III-4 inwhich X is I.

The compound of Formula III-4 is then oxidized, for example, via a Jonesoxidation reaction using chromium trioxide in a dilute sulfuric acid.This results in the formation of compound of Formula III-5.

Next, the compound of Formula III-5 may be reacted with a geraniolderivative in the presence of a solvent. For example, a compound ofFormula III-5 may be reacted with a geraniol derivative in DCC(dicyclohexylcarbodiimide) and acetonitrile (MeCN) at 0 to 25° C.Examples of geraniol derivatives include, but are not limited to:(2Z,6E)-methyl 8-hydroxy-2,6-dimethylocta-2,6-dienoate; (2E,6E)-methyl8-hydroxy-2,6-dimethylocta-2,6-dienoate;(2E,6E)-8-hydroxy-2,6-dimethylocta-2,6-dien-1-yl acetate;(2Z,6E)-8-hydroxy-2,6-dimethylocta-2,6-dien-1-yl acetate;(2Z,6E)-8-hydroxy-N-methoxy-N,2,6-trimethylocta-2,6-dienamide;(2Z,6E)-2,6-dimethylocta-2,6-diene-1,8-diol;(2Z,6E)-2,6-dimethylocta-2,6-diene-1,8-diol;(2E,6E)-8-hydroxy-2,6-dimethylocta-2,6-dienal; and(2Z,6E)-8-hydroxy-2,6-dimethylocta-2,6-dienal. This results in theformation of the compound of Formula III-6.

Then, the compound of Formula III-6 is mixed with water in an aqueouswork up. As a result, a transitional compound of Formula III-7 isformed, which then transitions to the compound of Formula III.

Further details regarding the reactions depicted in Scheme 4 can befound in Larock, J. Org. Chem. 2003, 68, 5936-5942; Li, Synthesis, 2007,3, 400-406; H. M. Nelson et al., 2009, supra; and Johansson et al.,2009, supra, the entire contents of all of which are incorporated hereinby reference.

Previous attempts to couple certain stannane compounds to iodoacid 6awere unsuccessful under standard cross-coupling conditions. (H. M.Nelson, et al., 2009, supra, and R. Larsson et al., 2009, supra.).Accordingly, a suitable protecting group strategy would need to bedevised for the carboxylic acid moiety of the Formula III compound. Inaccordance with the present invention, silyl esters were investigatedfor this purpose. In some embodiments, for example, tert-butyldimethylsilyl (TBS)-ester 6b is synthesized by treatment with TBSCl andimidazole, as shown in Scheme 5, below (E. J. Corey et al., J. Am. Chem.Soc. 1972, 94, 6190-6191, the entire contents of which are incorporatedherein by reference). In some embodiments, the silyl ester is prepareddirectly from iodoacid 6a (X=I) under slightly modified reactionconditions, i.e. using N,O-bis(tert-butyldimethylsilyl)acetimide.However, the yield over three steps may be significantly lower; ca. 10%.

In other embodiments of the present invention, a compound of Formula IIIis prepared following a reaction analogous to Scheme 3 above in whichcompound III-7 includes a trimethylsilyl (SiMe₃) protecting group,resulting in a compound of Formula III, where R⁸ is SiMe₃, as shown inScheme 6a. In some embodiments, compound III-7 (SiMe₃) is reacted withBTSA (bis-trimethylsilyl acetamide), and triethylamine (NEt₃) in tolueneat 100° C., as shown in Scheme 6b, below. In other embodiments compoundIII-7 (SiMe₃) is enantioenriched and chirality is transferred throughthe cyclization reaction to produce optically active, enantioenrichedcompound III (90%), as shown in Scheme 6b. In some embodiments the SiMe₃is removed, for example, by treatment with aqueous hydrogentetrafluoroborate (HBF₄) as shown in Scheme 6c.

In some embodiments of the present invention, a method of enriching foran enantiomer of Formula I is provided, including synthesizing acompound of Formula III in which one of R^(7′) and R^(8′) is a silylgroup and the other of R^(7′) and R^(8′) is hydrogen, followed byremoval of the silyl group to form an enantioselective compound, andthen reacting the compound of Formula II with the enantioselectivecompound, as shown in Scheme 7, below.

B. Compounds of Formula II

No successful cross-coupling reactions of methoxyacetylene orderivatives thereof to any vinyl or aryl halide have been reported.Accordingly, to utilized a cross-coupling reaction to form the compoundof Formula I, a different cross-coupling reactant would be needed. Tothat end, considering certain limited reports of tin and zincderivatives of commercial ethoxyacetylene in palladium-catalyzedcross-couplings, the present inventors devised a stannane-basedmethoxyacetylene derivative in the cross-coupling reactions describedherein with respect to the formation of the compound of Formula I. Insome embodiments of the present invention, therefore, the compound ofFormula I may be made following the reaction in Scheme 8 below. Thelimited reports of tin and zinc derivatives of commercialethoxyacetylene in palladium-catalyzed cross-couplings can be found inJ. A. Marshall in Organometallics in Synthesis: A Manual (Ed.: M.Schlosser) John Wiley & Sons Ltd., West Sussex, 2002, pp. 457; T.Sakamoto et al., Synlett 1992, 6, 502; T. Sakamoto, et al., Chem. Pharm.Bull, 1994, 42, 2032-2035; A. Löffler et al., Synthesis 1992, 5,495-498, the entire contents of all of which are incorporated herein byreference.

As shown in Scheme 8 above, when exposed to LiNEt₂ (lithiumdiethylamine) in THF (tetrahydrofuran),1,1-dimethoxy-2-chloro-acetaldehyde (compound 8) is transformed intolithium acetylide (compound 9), which can be quenched with tributyltinchloride (Bu₃SnCl) to safely produce a stannane-based derivative ofmethoxyacetylene (compound 10) (Formula II) at 78% yield in a singleoperation. An analogous preparation of a lithioethoxyacetylide isreported in S. Raucher et al., J. Org. Chem. 1987, 52, 2332-2333, theentire contents of which are incorporated herein by reference. In someembodiments, Bu₃SnCl is substituted with ZnCl₂ as further detailed inExample 8 (Bu₃SnCl) and Example 9 (ZnCl₂) (Negishi coupling). In otherembodiments, cross-coupling can be carried out using any suitablemethod—i.e., any of the standard Pd catalyzed cross-couplings. Examplesof Pd-catalyzed cross-coupling methods known in the art include: H(Sonigashira), ZnX (Negishi), SnR₃ (Stille), MgX (Kumada), and BR₃(Suzuki).

With reference to Scheme 9 below, exposure of silyl ester 6b andstannane-based compound 10 to Pd(PPh₃)₄ or Pd(Pt-Bu₃)₂ leads totransient formation of an enzyme 11. The Pd(PT-Bu3)2 catalyst isdisclosed in C. Dai, g. C. Fu, J. Am. Chem. Soc. 2001, 122, 2719-2724,the entire contents of which are incorporated herein by reference. Whileobservable by mass spectrometry and ¹H NMR analysis, direct isolation ofthe methoxyenyne compound 11 proved difficult. After optimization of thereaction conditions, aqueous work-up effected in situ desilylation andcyclization to afford a separable mixture of transtaganolide C (1a) andtranstaganolide D (1b) at 21% and 10% yield, respectively, usingPd(PPh₃)₄ catalyst (19% and 10% with Pd(Pt-Bu₃)₂ catalyst). Screening ofreaction conditions failed to improve the yields of transtaganolides 1aand 1b. The difficulty in achieving an efficient [5+2] annulation isattributed to several factors. It was found that the methoxyenynecompound 11 is unstable under the reaction conditions—i.e., modestextension of the reaction time (˜24 h) leads to non-productiveconsumption of the intermediate methoxyenyne compound 11. Additionally,the stannane-based compound 10 is itself unstable to Pd catalysis:addition of Pd(PPh₃)₄ to a solution of the stannane-based compound 10 inDMF (dimethylformamide) leads to consumption of the stannane-basedcompound 10 and the formation of oligomeric products.

The relative stereochemistry of synthetic transtaganolide C (1a) ofFormula I (Scheme 9) was unambiguously confirmed by X-raycrystallography, and synthetic transtaganolides C and D werespectroscopically indistinguishable from the naturally occurringisolates (FIGS. 1-4; Appendix). Crystallographic data (Appendix), havebeen deposited at the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK underthe deposition number 796908.

With reference to Scheme 10 below, basiliolide B (3a) of Formula I, wassynthesized using known geraniol derivative 12. Synthesis of thegeraniol derivative 12 is disclosed in H. Shibuya et al., Chem. Pharm.Bull. 1994, 42, 293-299, the entire contents of which are incorporatedherein by reference. In synthesizing the basiliolide B (3a), thegeraniol derivative (compound 12) was first coupled to an acidfunctional iodopyrone (compound 13) to form an ester compound (estercompound 7b) at high yield. This reaction is discussed in H. M. Nelsonet al., 2009, supra, and R. Larsson et al., 2009, supra.

Continuing in the synthesis of basiliolide B, the ester 7b is treatedwith N,O-bis(trimethylsilyl)acetamide (BSA or BTSA) and triethylamine(NEt₃), which resulting a Claisen/Diels-Alder cascade to yield theresulting acid 6c (a compound of Formula III), in a single operation andin 67% yield as a 2:1 mixture of diastereomers, as shown in Scheme 10.

Lowering the concentration of the ester in the reaction allowed for theDiels-Alder cycloaddition to occur in the same reaction mixture.Alternatively, microwave irradiation of the intermediate acid in CH₂Cl₂in a sealed vial at 165° C. for 48 hours also smoothly produces theDiels-Alder product. This represents an improvement over previous,two-step procedures that required isolation and/or manipulation of theClaisen products (e.g. Scheme 1), and is the first example in this areathat utilizes a more functionalized dienophile.

With reference to Scheme 10, following silylation of the free acid incompound 6c to form compound 6d, the resulting silyl ester (compound 6d)was exposed to the presently disclosed methoxy-alkynylation reactantsincluding stannane-based compound 10 and Pd(Pt-Bu₃)₂. Further details ofthe silylation reaction made be found in T. P. Mawhinney et al., J. Org.Chem. 1982, 47, 3336-3339, the entire contents of which are incorporatedherein by reference. The cross-coupling of compound 6d with compound 10,and the subsequent treatment with water of the crude product yieldresulted in the production and isolation of synthetic basiliolide B(compound 3a) and previously unreported epi-8-basiliolide B (compound14) in 5% and 14% yields, respectively, using Pd(PPh₃)₄ (6% and 12% withPd(PPh₃)₄). The isolated synthetic basiliolide B (3a) wasspectroscopically indistinguishable from the natural product isolatedfrom Thapsia sp (FIGS. 5-6; Appendix).

II. Synthesis of Compounds of Formula IV

In some embodiments of the present invention, compounds of Formula IVare synthesized for use in structure-function assays in view of thecharacterized potential of the transtaganolide and basiliolidecompounds. In some embodiments, compounds of Formula IV are synthesizedaccording to the reaction shown in Scheme 11, below.

With reference to Scheme 11, a compound of Formula IV-I is reacted witha compound of Formula IV-II to form a compound of formula IV,

wherein:

-   R_(a) is selected from the group consisting of hydrocarbyl,    substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and    substituted heteroatom-containing hydrocarbyl;-   W_(a) is selected from the group consisting of —OR^(X), —SR^(XX),    and —NR^(XXX)R^(XXXX), where each of R^(X), R^(XX), R^(XXX) and    R^(XXXX) is independently selected from the group consisting of    hydrogen, hydrocarbyl, substituted hydrocarbyl,    heteroatom-containing hydrocarbyl, and substituted    heteroatom-containing hydrocarbyl;-   each of R³ through R⁸ is selected from the group consisting of    hydrogen, hydrocarbyl, substituted hydrocarbyl,    heteroatom-containing hydrocarbyl, and substituted    heteroatom-containing hydrocarbyl;-   Z is selected from the group consisting of —O, —S and —NR²², wherein    R²² is selected from the group consisting of hydrocarbyl,    substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and    substituted heteroatom-containing hydrocarbyl;-   M is selected from the group consisting of Li, Na, hydrogen,    SiR¹²R¹⁴R¹⁵, SnR¹⁶R¹⁷R¹⁸, BR¹⁹R²⁰, MgX′₂ and ZnX″₂, wherein:    -   each of R¹³ through R¹⁸ is independently selected from the group        consisting of hydrocarbyl, and substituted hydrocarbyl,    -   each of R¹⁹ and R²⁰ is independently selected from the group        consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl,        heteroatom-containing hydrocarbyl, and substituted        heteroatom-containing hydrocarbyl, and    -   each of X′ and X″ is independently selected from the group        consisting of halogens;-   X is a halogen; and-   any two or more of R_(a) and R³ through R⁸ optionally combine to    form a ring.

The reaction of Scheme 11 may occur under varying suitable conditionswith varying suitable reagents as disclosed herein. For example, thereaction can occur in the presence of a palladium catalyst (e.g.,Pd(PPh₃)₄ or Pd(Pt-Bu₃)₂ in a suitable solvent and temperature. Examplesof solvents include, but are not limited to dimethylformamide (DMF),THF, acetonitrile, dichloromethane, dichloroethane, toluene, benzene,diethyl ether, DMSO, water, DME, DMA, cyclohexane, t-butyl methylether,carbon tetrachloride, chloroform, methanol, ethanol, heptane, pentane,hexanes, and combinations thereof. As discussed above, temperature willvary depending on the reagents selected.

In some embodiments, a compound of Formula IV in which R_(a) is a vinylgroup and W_(a) is —OMe (methoxy) is provided. In some embodiments thiscompound of Formula IV is synthesized following the reaction shown belowin Scheme 12. FIG. 16 shows a ¹H NMR spectrum of this Formula IVcompound.

In some embodiments, a compound of Formula IV in which R_(a) isethoxyacetylene and W_(a) is —OMe (methoxy) is provided. In someembodiments this compound of Formula IV is synthesized following thereaction shown below in Scheme 13. FIG. 17 shows a ¹H NMR spectrum ofthis Formula IV compound.

The following Examples are presented for illustrative purposes only, anddo not limit the scope or content of the present application.

EXAMPLES Materials and Methods

Unless otherwise stated, reactions were performed in flame-driedglassware under an argon or nitrogen atmosphere using dry deoxygenatedsolvents. Solvents were dried by passage through an activated aluminacolumn under argon. Pd(t-Bu₃P)₂, N,N′-dicyclohexylcarbodiimide,1,1-dimethoxy-2-chloro-acetaldehyde, N,O-bis(trimethylsilyl)acetamide,N-methyl-N-(tert-butyldimethylsilyl)triflouroacetamide, and imidazolewere purchased from Sigma-Aldrich Chemical Company and used as received.Pd(PPh₃)₄ was prepared using known methods—e.g., M. R. Mason et al.,Organometallics, 1992, 11, 2212-2220, the entire contents of which isincorporated herein by reference. Thin-layer chromatography (TLC), bothpreparatory and analytical, were performed using E. Merck silica gel 60F254 precoated plates (0.25 mm) and visualized by UV fluorescencequenching, p-anisaldehyde, I₂, or KMnO₄ staining (M. R. Mason et al.1992, supra). ICN Silica gel (particle size 0.032-0.063 mm) was used forflash chromatography.

¹H NMR, and ¹³C NMR spectra (FIGS. 1-15), were recorded on a VarianMercury 300 (at 300 MHz) or on a Varian Unity Inova 500 (at 500 MHz). ¹HNMR spectra are reported relative to CDCl₃ (7.26 ppm). Data for ¹H NMRspectra are reported as follows: chemical shift, multiplicity, couplingconstant (Hz), integration. Multiplicities are reported as follows:s=singlet, d=doublet, t=triplet, q=quartet, sept.=septet, m=multiplet,comp. m=complex multiplet, app.=apparent, bs=broad singlet. ¹³C NMRspectra are reported relative to CDCl₃ (77.0 ppm).

Fourier Transform Infrared (FTIR) spectroscopy spectra were recorded ona Perkin Elmer SpectrumBX spectrometer and are reported in frequency ofabsorption (cm⁻¹). High Resolution Mass Spectrometry (HRMS) data wereacquired using an Agilent 6200 Series TOF with an Agilent G1978AMultimode source in electrospray ionization (ESI), atmospheric pressurechemical ionization (APCI) or multimode-ESI/APCI. Crystallographic datawere obtained from the Caltech X-ray Diffraction Facility. FTIR and HRMSdata are provided in the Appendix.

Experimental Procedures Example 1

Iodoacid 6a. To a solution of 7a (6.2 g, 15 mmol, 1.0 equiv) in toluene(75 mL) at 25° C. in a sealed tube was addedN,O-bis(trimethylsilyl)acetamide (BTSA) (7.2 mL, 30 mmol 2.0 equiv). Tothe reaction mixture was then added triethylamine (0.41 mL, 3.0 mmol,0.20 equiv). The reaction mixture was heated to 110° C. and stirred for20 minutes. The mixture was cooled to 25° C. and diluted with toluene(750 mL). The reaction mixture was then re-heated to 100° C. and stirredfor 4 days. The mixture was cooled to 25° C. and extracted withsaturated aqueous NaHCO₃ (7×100 mL). To the combined aqueous extractswas added 1 M aqueous HCl until pH=3. The aqueous layer was thenextracted with ethyl acetate (3×100 mL). The combined organics weredried over Na₂SO₄, and concentrated by rotary evaporation to yield 3.2 g(51%) of 6a as a tan foam.

Major: ¹H NMR (500 MHz, CDCl₃) δ 6.93 (d, J=6.5 Hz, 1H), 6.01 (dd,J=10.5, 17.5 Hz, 1H), 5.05-5.02 (m, 2H), 3.00-2.94 (m, 2H), 1.68-1.42(m, 5H), 1.29 (s, 3H), 1.08 (s, 3H), 1.00 (s, 3H); ¹³C NMR (125 MHz,CDCl₃) δ 172.7, 170.5, 148.0, 140.0, 111.5, 97.9, 84.7, 59.4, 56.4,47.9, 39.8, 36.8, 29.8, 24.5, 20.5, 18.4. Minor: ¹H NMR (500 MHz, CDCl₃)δ 6.93 (d, J=6.5 Hz, 1H), 6.35 (dd, J=11.0, 17.5 Hz, 1H), 5.09 (d,J=11.0 Hz, 1H), 5.05-5.02 (m, 1H), 3.00-2.94 (m, 2H), 1.92-1.90 (m, 1H),1.68-1.42 (m, 4H), 1.26 (s, 3H), 1.08 (s, 3H), 1.00 (s, 3H).

¹³C NMR (125 MHz, CDCl₃) δ 172.7, 170.4, 140.4, 140.3, 113.7, 97.4,84.8, 61.0, 56.6, 48.0, 39.3, 38.7, 37.0, 29.8, 29.5, 24.5, 20.6. FTIR(Neat Film NaCl) 3081, 2967, 2931, 1754, 1741, 1738, 1732, 1708, 1414,1396, 1219, 1175, 964, 916, 874, 797, 736 cm⁻¹; HRMS(Multimode-ESI/APCI) m/z calc'd for C₁₇H₂₁O₄I [M+H]⁺: 417.0557, found417.0553.

Example 2

tert-Butyldimethylsilyl ester 6b. To a solution of 6a (46 mg, 0.11 mmol,1.0 equiv) in dimethylformamide (0.30 mL) were addedtert-butyldimethylsilylchloride (84 mg, 0.56 mmol, 5.0 equiv) andimidazole (76 mg, 1.1 mmol, 10 equiv). The reaction was warmed to 40° C.and then stirred for 12 hours. The reaction mixture was then dilutedwith saturated aqueous NaCl (1 mL) and extracted with diethylether/hexane (1:1) (3×2 mL). The combined organic extracts were washedwith saturated aqueous KHSO₄ (1 mL) and then with saturated aqueous NaCl(3×1 mL). The combined organics were dried over Na₂SO₄, and concentratedby rotary evaporation. The crude oil was chromatographed (ethyl acetatein hexane 10

50% on SiO₂) to yield 39 mg (66%) of 6b as a white powder.

Procedure 2. To a solution of 6a (180 mg, 0.43 mmol, 1.0 equiv) inacetonitrile (0.43 mL) was addedN-methyl-N-(tert-butyldimethylsilyl)trifluoroacetamide (1.0 g, 4.3 mmol,10 equiv) at 25° C. and stirred for 15 minutes. The reaction mixture wasdiluted with saturated aqueous NaCl (1 mL) and extracted with diethylether/hexane (1:1) (3×2 mL). The combined organic extracts were washedwith saturated aqueous KHSO₄ (1 mL) and then with saturated aqueous NaCl(3×1 mL). The combined organics were dried over Na₂SO₄, and concentratedby rotary evaporator. The crude oil was chromatographed (ethyl acetatein hexane 10

50% on SiO₂) to yield 150 mg (64%) of 6b as a white powder.

FIG. 7 shows a ¹H NMR spectrum for tert-butyldimethylsilyl ester (6b).Major: ¹H NMR (500 MHz, CDCl₃) δ 6.90 (d, J=6.5 Hz, 1H), 6.03 (dd,J=11.0, 17.5 Hz, 1H), 4.99 (d, J=17.5 Hz, 1H), 4.99 (d, J=11.0 Hz, 1H),2.95 (s, 1H), 2.93 (d, J=6.5 Hz, 1H), 1.66-1.39 (m, 4H), 1.32-1.29 (m,1H), 1.26 (s, 3H), 1.07 (s, 3H), 0.99 (s, 3H), 0.91 (s, 9H), 0.29 (s,3H), 0.27 (s, 3H); FIG. 8 shows a ¹³C NMR spectrum fortert-butyldimethylsilyl ester (6b). ¹³C NMR (125 MHz, CDCl₃) δ 170.6,169.1, 149.2, 139.7, 110.5, 98.7, 84.6, 60.4, 56.7, 48.2, 40.1, 38.7,36.9, 29.8, 25.5, 24.5, 20.7, 18.1, 17.5, −4.8, −4.8.

Minor: ¹H NMR (500 MHz, CDCl₃) δ 6.90 (d, J=6.5 Hz, 1H), 6.40 (dd,J=11.0, 17.5 Hz, 1H), 5.05 (dd, J=1.0, 11.0 Hz, 1H), 5.03-4.98 (m, 1H),2.91 (d, J=6.5 Hz, 1H), 2.86 (s, 1H), 1.85 (dt, J=3.5, 13.5 Hz, 1H),1.66-1.39 (m, 3H), 1.36 (s, 3H), 1.34-1.29 (m, 1H), 1.05 (s, 3H), 0.98(s, 3H), 0.90 (s, 9H), 0.30 (s, 3H), 0.28 (s, 3H). ¹³C NMR (125 MHz,CDCl₃) δ 170.6, 169.3, 141.3, 139.9, 112.9, 98.3, 84.7, 61.8, 56.8,48.4, 39.6, 39.4, 37.2, 29.6, 25.6, 25.4, 24.4, 20.8, 17.5, −4.9, −4.9.

FTIR (Neat Film NaCl) 3959, 2929, 2857, 1760, 1716, 1708, 1471, 1284,1250, 1173, 1022, 967, 840, 827, 789, 736 cm⁻¹. HRMS(Multimode-ESI/APCI) m/z calc'd for C₂₃H₃₆O₄ISi [M+H]⁺: 531.1422, found531.1432 (Appendix.)

Example 3

Transtaganolides (1). In a nitrogen filled glovebox, to a solution of 6b(16 mg, 0.030 mmol, 1.0 equiv) and Pd(PPh₃)₄ (35 mg, 0.030 mmol, 1equiv) in dimethylformamide (0.30 mL, 0.10 M) was addedtributyl(2-methoxyethynyl)stananne (10) (32 mg, 0.090 mmol, 3.0 equiv).The reaction was stirred at 31° C. for 16 h. The reaction mixture wasthen treated with water (30 μL) and stirred at room temperature for 1hour. That mixture was diluted with ethyl acetate (1 mL) and washed withwater (4×0.5 mL) and concentrated by rotary evaporation. The crude oilwas purified by normal phase HPLC to yield 2.1 mg (21%) oftranstaganolide C (1a) and 1.1 mg (10%) of transtaganolide D (1b) aswhite powders. Crystals were grown by slow evaporation fromacetonitrile.

Procedure 2. In a nitrogen filled glovebox, to a solution of 6b (16 mg,0.030 mmol, 1.0 equiv) and Pd(t-Bu₃P)₂ (15 mg, 0.030 mmol, 1.0 equiv) indimethylformamide (0.30 mL, 0.10 M) was addedtributyl(2-methoxyethynyl)stannane (10) (32 mg, 0.090 mmol, 3.0 equiv).The reaction was stirred at 31° C. for 10 hours. The reaction mixturewas then treated with water (30 μL) and stirred at room temperature for1 hour. The mixture was diluted with ethyl acetate (1 mL) and washedwith water (4×0.5 mL) and concentrated by rotary evaporation. The crudeoil was purified by normal phase HPLC to yield 2.0 mg (19%) oftranstaganolide C (1a) and 1.0 mg (10%) of transtaganolide D (1b) aswhite powders.

Transtaganolide C (1a). FIG. 1 shows a ¹H NMR spectrum ofTranstaganolide C (1a). ¹H NMR (500 MHz, CDCl₃)

6.07 (dd, J=1.5, 6.5 Hz, 1H), 5.80 (dd, J=11.0, 17.5 Hz, 1H), 5.07 (d,J=17.5 Hz, 1H), 5.03 (d, J=11.0 Hz, 1H), 5.00 (d, J=1.5 Hz, 1H), 3.71(s, 3H), 3.23 (s, 1H), 3.06 (d, J=6.5 Hz, 1H), 1.71-1.63 (m, 3H), 1.60(s, 3H), 1.44 (m, 1H), 1.30 (m, 1H), 1.08 (s, 3H), 0.97 (s, 3H).

FIG. 2 shows a ¹³C NMR spectrum of Transtaganolide C (1a). ¹³C NMR (125MHz, CDCl₃) δ 171.8, 162.3, 156.7, 146.5, 138.0, 123.6, 112.8, 87.3,79.3, 56.3, 53.8, 50.6, 48.1, 38.4, 38.3, 33.3, 29.9, 24.8, 19.9, 19.2.

FTIR (Neat Film NaCl) 2965, 2928, 2872, 1791, 1761, 1668, 1619, 1456,1334, 1267, 1233, 1178, 1115, 970, 954, 828 cm⁻¹. HRMS(Multimode-ESI/APCI) m/z calc'd for C₂₀H₂₄O₅ [M+H]⁺: 345.1697, found345.1703; MP: 135-160° C. (at these temperatures decarboxylation isthought to occur, as the crystalline sample and the resulting liquidwere vigorously bubbling throughout the measurement, thus it is unclearwhether thermal decomposition precluded state change) (Appendix).

Transtaganolide D (1b). FIG. 3 shows a ¹H NMR spectrum ofTranstaganolide D (1b). ¹H NMR (500 MHz, CDCl₃) δ 7.00 (dd, J=11.0, 17.5Hz, 1H), 6.09 (dd, J=1.0, 6.5 Hz, 1H), 5.15 (dd, J=1.0, 11.0 Hz, 1H),5.05 (dd, J=1.0, 17.5 Hz, 1H), 5.02 (d, J=1.0 Hz, 1H), 3.73 (s, 3H),3.13 (s, 1H), 3.06 (d, J=6.5 Hz, 1H), 1.91 (dt, J=3.5, 13.5 Hz, 1H),1.64 (dquint, J=3.0, 13.5 Hz, 1H), 1.58 (m, 1H), 1.39 (dt, J=3.5, 13.5Hz, 1H), 1.33 (dd, J=4.5, 13.5 Hz, 1H), 1.22 (s, 3H), 1.04 (s, 3H), 0.97(s, 3H).

FIG. 4 shows a ¹³C NMR spectrum of Transtaganolide D (1b). ¹³C NMR (125MHz, CDCl₃) δ 171.7, 162.6, 156.7, 142.9, 137.7, 123.9, 112.1, 87.3,79.4, 56.3, 54.0, 53.3, 48.4, 40.5, 38.4, 33.3, 29.9, 28.5, 24.8, 20.5.

FTIR (Neat Film NaCl) 2964, 2929, 2872, 1764, 1760, 1738, 1667, 1620,1467, 1334, 1267, 1235, 1195, 1177, 1106, 1009, 954, 827 cm⁻¹. HRMS(Multimode-ESI/APCI) m/z calc'd for C₂₀H₂₄O₅ [M+H]⁺: 345.1697, found345.1698; MP: 135-160° C. (at these temperatures decarboxylation isthought to occur, as the crystalline sample and the resulting liquidwere vigorously bubbling throughout the measurement; thus it is unclearwhether thermal decomposition precluded state change) (Appendix).

Example 4

Ester 7b. To a solution of geraniol derivative 12 (140 mg, 0.70 mmol,1.0 equiv) and iodopyrone acid 13 (210 mg, 0,70 mmol, 1.0 equiv) inacetonitrile (7.0 ml) was added N,N′-dicyclohexylcarbodiimide (190 mg,0.91 mmol, 1.3 equiv) at 0° C. The reaction was warmed to 25° C. andstirred for seven additional hours. The reaction mixture was thenfiltered through a pad of Celite, and then concentrated by rotaryevaporation. The crude reaction mixture was then chromatographed (ethylacetate in hexane 0

30% on SiO₂) to give 300 mg (94%) of 7b as a pale yellow oil.

FIG. 9 shows a ¹H NMR spectrum of ester 7b. ¹H NMR (500 MHz, CDCl₃)

7.45 (d, J=10.0 Hz, 1H), 6.70 (tq, J=1.5, 7.5 Hz, 1H), 6.06 (d, J=10.0Hz, 1H), 5.35 (tq, J=1.5, 7.0 Hz, 1H), 4.67 (d, J=7.0 Hz, 2H), 3.77 (s,2H), 3.72 (s, 3H), 2.30 (q, J=7.5 Hz, 2H), 2.16 (t, J=7.5 Hz, 2H), 1.83(q, J=1.5 Hz, 3H), 1.72 (q, J=1.5 Hz, 3H).

¹³C NMR (125 MHz, CDCl₃) δ 168.5, 166.6, 160.3, 157.9, 151.2, 142.0,141.3, 128.0, 118.3, 116.1, 70.6, 62.5, 51.7, 42.6, 38.0, 26.8, 16.5,12.4.

FTIR (Neat Film NaCl) 2988, 2950, 1738, 1714, 1438, 1366, 1268, 1232,1126, 1082, 1023, 955, 745 cm⁻¹. HRMS (Multimode-ESI/APCI) m/z calc'dfor C₁₈H₂₅NO₆I [M+NH₄]⁺: 478.0725 (Appendix).

Example 5

Iodoacid 6c. To a solution of 7b (96 mg, 0.21 mmol, 1.0 equiv) intoluene (1.1 mL) in a sealed tube were successively added triethylamine(6.0 μL, 0.042 mmol, 0.20 equiv) and N,O-bis(trimethylsilyl)acetamide(100 μL, 0.42 mmol, 2.0 equiv). The reaction mixture was heated to 110°C. and stirred for 20 minutes, then cooled to 25° C. The reactionmixture was diluted with toluene (250 ml) and heated to 100° C. for 48hours. The reaction was then cooled to 25° C., the solvent removed byrotary evaporation, and the crude residue chromatographed (hexane/ethylacetate/acetic acid, 1:1:0.01 on SiO₂) to give 64 mg (67%) of 6c as acolorless foam.

FIG. 10 shows a ¹H NMR spectrum of iodoacid 6c. Major: ¹H NMR (500 MHz,CDCl₃) δ 6.93 (d, J=6.5 Hz, 1H), 6.02 (dd, J=10.5, 17.5 Hz, 1H),5.07-5.03 (m, 2H), 3.72 (s, 3H), 3.56-3.53 (m, 1H), 3.03 (s, 1H),2.40-2.33 (m, 1H), 1.77-1.56 (m, 4H), 1.32 (s, 3H), 1.30 (s, 3H). FIG.11 shows a ¹³C NMR spectrum of iodoacid 6c. ¹³C NMR (125 MHz, CDCl₃) δ174.8, 169.2, 169.1, 147.9, 139.7, 111.6, 99.2, 84.2, 59.2, 53.0, 52.6,47.8, 44.5, 40.0, 38.1, 20.8, 18.4.

Minor: ¹H NMR (500 MHz, CDCl₃) δ 6.93 (d, J=6.5 Hz, 1H), 6.33 (dd,J=11.0, 17.5 Hz, 1H), 5.10 (d, J=11.0 Hz, 1H), 5.07-5.03 (m, 1H), 3.72(s, 3H), 3.56-3.53 (m, 1H), 2.97 (s, 1H), 2.40-2.33 (m, 1H), 1.98-1.95(m, 1H), 1.77-1.56 (m, 3H), 1.30 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ174.8, 169.1, 169.0, 140.4, 140.0, 113.5, 98.8, 84.3, 60.6, 52.7, 48.0,39.45, 38.5, 29.8, 20.8, 20.8, 20.8.

FTIR (Neat Film NaCl) 3080, 2951, 1756, 1739, 1734, 1700, 1559, 1506,1457, 1211, 911, 756 cm⁻¹; HRMS (Multimode-ESI/APCI) m/z calc'd forC₁₈H₂₂O₆I [M+H]⁺: 461.0456, found 461.0460 (Appendix).

Example 6

tert-Butyldimethylsilyl ester 6d. To a solution of 6c (89 mg, 0.11 mmol,1.0 equiv) in dimethylformamide (0.52 mL) were addedtert-butyldimethylsilylchloride (150 mg, 0.97 mmol, 5.0 equiv) andimidazole (130 mg, 1.9 mmol, 10 equiv). The reaction mixture was warmedto 40° C. and stirred for 3 hours. The crude mixture was then dilutedwith saturated aqueous NaCl (1 mL) and extracted with diethylether/hexane (1:1) (3×2 mL). The combined organic extracts were washedwith saturated aqueous NaCl (3×1 mL), dried over Na₂SO₄, andconcentrated by rotary evaporation to yield 76 mg (68%) of 6d as a paleyellow powder.

Procedure 2. To a solution of 6c (61 mg, 0.13 mmol, 1 equiv) inacetonitrile (0.13 mL, 1.0 M) was addedN-methyl-N-(tert-butyldimethylsilyl)trifluoroacetamide (320 mg, 1.3mmol, 10 equiv) at 25° C. and stirred for 15 minutes. The reactionmixture was diluted with saturated aqueous NaCl (1 mL) and extractedwith diethyl ether/hexane (1:1) (3×2 mL). The combined organic extractswere washed with saturated aqueous KHSO₄ (1 mL) and then with saturatedaqueous NaCl (3×1 mL). The combined organics were dried over Na₂SO₄, andconcentrated by rotary evaporator. The crude oil was chromatographed(ethyl acetate in hexane 10

50% on SiO₂) to yield 51 mg (66%) of 6d as a white powder.

FIG. 12 shows a ¹H NMR spectrum of tert-Butyldimethylsilyl ester 6d.Major: ¹H NMR (500 MHz, CDCl₃)

6.92 (d, J=6.5 Hz, 1H), 6.04 (dd, J=10.5, 17.5 Hz, 1H), 5.01 (d, J=10.5Hz, 1H), 5.01 (d, J=17.5 Hz, 1H), 3.72 (s, 3H), 3.53 (d, J=6.5 Hz, 1H),2.98 (s, 1H), 2.38-2.31 (m, 1H), 1.76-1.54 (m, 4H), 1.31 (s, 3H), 1.37(s, 3H), 0.90 (s, 9H), 0.29 (s, 3H), 0.26 (s, 3H). FIG. 13 shows a ¹³CNMR spectrum of tert-Butyldimethylsilyl ester 6d. ¹³C NMR (125 MHz,CDCl₃) δ 174.9, 169.1, 168.9, 1489, 139.4, 110.7, 99.9, 84.2, 60.4,53.0, 52.7, 48.0, 44.7, 40.2, 38.5, 25.5, 20.9, 18.2, 17.5, −4.80,−4.80.

Minor: ¹H NMR (500 MHz, CDCl₃) δ 6.92 (d, J=6.5 Hz, 1H), 6.37 (dd,J=11.0, 17.5 Hz, 1H), 5.06 (d, J=11.0 Hz, 1H), 5.03-4.99 (m, 1H), 3.72(s, 3H), 3.51 (d, J=6.5 Hz, 1H), 2.90 (s, 1H), 2.38-2.31 (m, 1H),1.92-1.88 (m, 1H), 1.76-1.54 (m, 3H), 1.38 (s, 3H), 1.29 (s, 3H), 0.89(s, 9H), 0.29 (s, 3H), 0.28 (s, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 174.9,169.1, 169.1, 168.9, 141.0, 139.7, 113.0, 99.5, 84.3, 61.8, 52.9, 48.3,39.6, 39.0, 29.7, 25.3, 20.9, 20.8, 17.5, −4.90, −4.90.

IR (Neat Film NaCl) 2951, 2928, 2856, 1767, 1733, 1717, 1447, 1274,1251, 1215, 1191, 968, 843, 828, 792, 736 cm⁻¹; HRMS(Multimode-ESI/APCI) m/z calc'd for C₂₄H₃₆O₆ISi [M+H]⁺: 575.1320, found575.1317 (Appendix).

Example 7

Basiliolides (3a, 14). In a nitrogen filled glovebox, to a solution of6d (15 mg, 0.030 mmol, 1.0 equiv) and Pd(PPh₃)₄ (35 mg, 0.030 mmol, 1.0equiv) in dimethylformamide (0.30 mL, 0.10 M) was addedtributyl(2-methoxyethynyl)stananne (10) (53 mg, 0.050 mmol, 5.0 equiv).The reaction was stirred at 30° C. for 16 hours, then treated with water(30 μL) and stirred at 25° C. for an additional 1 hour. The mixture wasthen diluted with ethyl acetate (1 mL) and washed with water (4×0.5 mL)and concentrated by rotary evaporation. The crude oil was purified bynormal phase HPLC to yield 0.6 mg (6%) of basiliolide B (3a) and 1.2 mg(12%) of epi-8-basiliolide B (14) as white powders.

Procedure 2. In a nitrogen filled glovebox, to a solution of 6b (16 mg,0.030 mmol, 1.0 equiv) and Pd(t-Bu₃P)₂ (15 mg, 0.030 mmol, 1.0 equiv) indimethylformamide (0.30 mL, 0.10 M) was addedtributyl(2-methoxyethynyl)stananne (43 mg, 0.12 mmol, 4.0 equiv). Thereaction was stirred at 30° C. for 10 hours, and then an additionaliquot (22 mg, 0.060 mmol, 2.0 equiv) of stannane 10 was added andstirred for an additional two hours. The reaction was treated with water(30 μL) and stirred at 25° C. for an additional 1 hour. The crudereaction mixture was diluted with ethyl acetate (1 mL) and washed withwater (4×0.5 mL) and concentrated by rotary evaporation. The crude oilwas purified by normal phase HPLC to yield 0.6 mg (5%) of basiliolide B(3a) and 1.6 mg (14%) of epi-8-basiliolide B (14) as white powders.

FIG. 5 shows a ¹H NMR spectrum of Basiliolide B (3a). ¹H NMR (500 MHz,CDCl₃) δ 7.00 (dd, J=11.5, 18 Hz, 1H), 6.08 (d, J=5.5 Hz, 1H), 5.17 (d,J=11.5 Hz, 1H), 5.06 (d, J=18 Hz, 1H), 4.96 (s, 1H), 3.72 (s, 3H), 3.71(s, 3H), 3.67 (d, J=5.5 Hz, 1H), 3.17 (s, 1H), 2.29 (dd, J=5.0 Hz, 1H),1.96 (dt, J=3.0 Hz, 13.5 Hz, 1H), 1.74-1.65 (m, 2H), 1.54-1.48 (m, 1H),1.30 (s, 3H), 1.24 (s, 3H). FIG. 6 shows a ¹³C NMR spectrum ofBasiliolide B (3a). ¹³C NMR (125 MHz, CDCl₃) δ 175.2, 170.1, 162.3,156.7, 142.7, 139.2, 123.4, 112.3, 87.0, 79.2, 56.4, 53.3, 52.9, 50.0,44.8, 44.7, 40.2, 38.5, 28.6, 21.0, 20.8.

FTIR (Neat Film NaCl) 2951, 2875, 1791, 1761, 1771, 1767, 1733, 1668,1663, 1456, 1334, 1262, 1230, 1213, 1180, 1107, 1011, 960, 908, 833, 736cm⁻¹. HRMS (Multimode-ESI/APCI) m/z calc'd for C₂₁H₂₄O₇ [M+H]⁺:389.1595, found 389.1599 (Appendix).

¹H NMR (500 MHz, CDCl₃) δ 6.06 (d, J=6.0 Hz, 1H), 5.80 (dd, J=10.5, 17.5Hz, 1H), 5.09 (d, J=10.5 Hz, 1H), 5.05 (d, J=17.5 Hz, 1H), 4.94 (s, 1H),3.71 (s, 3H), 3.70 (s, 3H), 3.66 (d, J=6.0 Hz, 1H), 3.26 (s, 1H), 2.25(dd, J=7.0, 12.0 Hz, 1H), 1.79-1.67 (m, 4H), 1.61 (s, 3H), 1.34 (s, 3H).¹³C NMR (125 MHz, CDCl₃) δ 175.1, 170.1, 162.0, 146.2, 139.5, 123.2,113.0, 87.0, 79.0, 56.3, 52.9, 50.5, 49.9, 44.7, 44.6, 38.5, 38.2, 21.0,20.3, 19.3.

FTIR (Neat Film NaCl) 2980, 2951, 2929, 1770, 1767, 1761, 1732, 1668,1619, 1442, 1335, 1261, 1219, 1182, 1106, 971, 960, 918, 834, 732 cm⁻¹.HRMS (Multimode-ESI/APCI) m/z calc'd for C₂₁H₂₄O₇ [M+H]⁺: 389.1595,found 389.1604 (Appendix).

Example 8

Tributyl(2-methoxyethynyl)stannane (10). To a solution of freshlydistilled diethylamine (9.6 mL, 92 mmol, 3.9 equiv) in tetrahydrofuran(300 mL) at 0° C. was added n-butyllithium (2.5 M in hexanes, 32 mL, 80mmol, 3.4 equiv). After stirring for 10 min,1,1-dimethoxy-2-chloro-acetaldehyde (4.0 mL, 26 mmol, 1.1 equiv) wasadded dropwise to the reaction mixture. The reaction was stirred for 2hours at 0° C. Tributyltin chloride (6.2 mL, 24 mmol, 1.0 equiv) wasthen added to the reaction mixture. The reaction was warmed to 23° C.over 1 hour and stirred for 8 hours. The volatiles were removed in vacuoand the reaction mixture was re-suspended in hexane (30 mL) and filteredthrough a glass frit under an argon atmosphere. The solution was thenre-concentrated by rotary evaporation and distilled by Kugelrohr toyield 6.4 g (78%) of 10 as a colorless oil.

¹H NMR (500 MHz, CDCl₃) δ 3.87 (s, 3H), 1.54 (m, 6H), 1.33 (sextet,J=7.5 Hz, 6H), 0.94 (m, 6H), 0.90 (t, J=7.5 Hz, 9H).). ¹³C NMR (125 MHz,CDCl₃) δ 114.7, 65.8, 31.5, 28.9, 27.0, 13.7, 11.2.

FTIR (Neat Film NaCl) 2955, 2927, 2871, 2161, 1457, 1208, 1126, 910, 865cm⁻¹; Elemental analysis found: C, 52.40%; H, 8.54%. Calculated forC₁₅H₃₀OSn: C, 52.20%; H, 8.76% (Appendix).

Example 9

Zn acetaldehyde was made using Negishi cross-coupling. In a nitrogenfilled glove box, a flask was charged with THF (1.15 mL) anddiethylamine (0.40 mL). The reaction mixture was cooled to 0_C andn-BuLi (0.34 mL of 10M solution in hexanes) was slowly added. Afterstirring for 2 hours, chlorodimethoxyacetaldehyde (1 mmol 0.114 mL) wasadded slowly. Subsequent to stirring for 2 hours, the reaction mixturewas transferred to a flask charged with anhydrous ZnCl₂ (150 mg) andstirred at 0° C. for an additional 20 minutes. Concurrently, a flamedried microwave vial was charged with Pd₂(dba)₃ (0.9 mg, 0.05 equiv.),Xantphos (20 uL, 0.10 equiv), THF (0.50 mL), and iodoacid (1 equiv).After stirring for 2 hours, the crude Zn acetaldehyde (0.03 mL) wasadded via syringe into the microwave vial, and the reaction mixturesealed. Using microwaves, the reaction was heated to 100° C. for 2minutes. After cooling of the reaction mixture, the reaction was passedthrough a short pad of silica, diluted with acetonitrile. 100 uL of pH 7phosphate buffer was added and the reaction was stirred for 30 minutesat room temperature. Following normal phase HPLC, transtaganolides C andD were isolated in 21% and 10% yield. The synthetic transtaganolides arespectroscopically indistinguishable from the natural isolates.

Example 10

Trimethylsilyl iodoacid. 1-trimethylsilyl geraniol (1 mmol, 1 equiv) wasadded to a solution if iodoacid (1 mmol, 1 equiv) in acetonitrile (10mL) at 0° C. DCC (1.1 mmol, 1.1 equiv) was added and the reaction wasstirred for 1 hour. The reaction mixture was then dilated with ethylacetate and washed with 1% HCl (aq.) (3×100 mL). The organic layer wasdried with MgSO₄, and solvent was removed by rotary evaporation. Theresulting amber syrup was chromatographed on SiO2, using 25% ethylacetate in hexanes as an eluent, to produce the pyrone ester in 96%yield. A ¹H NMR spectrum of this SIM_(E3) pyrone ester is shown in FIG.14. The enantiomeric excess was determined by chiral SFC (super criticalfluid chromatography) and comparison to a racemic sample. SFC isdisclosed in C. White J. Chromatogr. A 2005, 1074, 163-173.

The Ireland-Claisen/Diels-Alder cyclization is the same for SiMe₃ pyroneester as for ester 7b, as disclosed herein (Scheme 4, Example 4, withreference to Larock, J. Org. Chem. 2003, 68, 5936-5942; Li, Synthesis,2007, 3, 400-406; H. M. Nelson et al., 2009, supra; and Johansson etal., 2009), to produce the iodoacid-SiMe₃. The ¹H NMR spectrum is shownin FIG. 15.

Removal of the SiMe₃. Trimethylsilyl-iodoacid (25 mg) was dissolved inacetonitrile (1 mL) and HBF₄ (aq.) (0.05 mL) was added. The reactionmixture was stirred for 3 hours at 25° C. The reaction mixture was thendiluted with ethyl acetete and washed with 1% HCl (aq.) 3×1 mL). Theorganic layer was dried with MgSO₄, and solvent was removed by rotaryevaporation. The resulting amber syrup was chromatographed on SiO₂,using 25% ethyl acetate in hexanes as an eluent, to produce the iodoacidin 96% yield. The compound was spectroscopically identical to thepreviously prepared racemic compound.

As disclosed throughout and evidenced by the NMR spectra of FIGS. 1-6,synthetic compounds of Formula I are provided. Additionally methods ofsynthesizing compounds of Formula I are provided including reactingcompounds of Formula II and Formula III. Furthermore, methods areprovided for using silyl compounds for synthesizing enantiomericenrichment of a compound of Formula I. Accordingly, synthetic compoundsand the method of synthesis of the present invention, provide increasedquantities and enrichment of desired compounds of Formula I, such asbasiliolides and transtaganolides.

While the present invention has been illustrated and described withreference to certain exemplary embodiments, those of ordinary skill inthe art will understand that various modifications and changes may bemade to the described embodiments without departing from the spirit andscope of the present invention, as defined in the following claims.

1-18. (canceled)
 19. A compound, comprising a synthetic compoundrepresented by Formula IV:

wherein: R_(a) is selected from the group consisting of hydrocarbyl,substituted hydrocarbyl, heteroatom-containing hydrocarbyl, andsubstituted heteroatom-containing hydrocarbyl; W_(a) is selected fromthe group consisting of —OR^(X), —SR^(XX), and —NR^(XXX)R^(XXXX), whereeach of R^(X), R^(XX), R^(XXX) and R^(XXXX) is independently selectedfrom the group consisting of hydrogen, hydrocarbyl, substitutedhydrocarbyl, heteroatom-containing hydrocarbyl, and substitutedheteroatom-containing hydrocarbyl; each of R³ through R⁸ is selectedfrom the group consisting of hydrogen, hydrocarbyl, substitutedhydrocarbyl, heteroatom-containing hydrocarbyl, and substitutedheteroatom-containing hydrocarbyl; Z is selected from the groupconsisting of —O, —S and —NR²², wherein R²² is selected from the groupconsisting of hydrocarbyl, substituted hydrocarbyl,heteroatom-containing hydrocarbyl, and substituted heteroatom-containinghydrocarbyl; any two or more of R_(a) and R³ through R⁸ optionallycombine to form a ring.
 20. The compound of claim 19, wherein R_(a) isan alkoxy.
 21. The compound of claim 19, wherein W_(a) is —OR^(X) inwhich R^(X) is a silyl ether moiety.
 22. The compound of claim 21,wherein the silyl ether moiety is a tert-butyl dimethyl silyl ethermoiety or a trimethyl silyl ether moiety.
 23. The compound of claim 20,wherein W_(a) is —OR^(X) in which R^(X) is a silyl ether moiety.
 24. Thecompound of claim 23, wherein the silyl ether moiety is a tert-butyldimethyl silyl ether moiety or a trimethyl silyl ether moiety.
 25. Amethod of synthesizing a compound of Formula IV, the method comprisingreacting a compound of Formula IV-I with a compound of Formula IV-IIaccording to reaction scheme 11 to form the compound of Formula IV:

wherein: R_(a) is selected from the group consisting of hydrocarbyl,substituted hydrocarbyl, heteroatom-containing hydrocarbyl, andsubstituted heteroatom-containing hydrocarbyl; W_(a) is selected fromthe group consisting of —OR^(X), —SR^(XX), and —NR^(XXX)R^(XXXX), whereeach of R^(X), R^(XX), R^(XXX) and R^(XXXX) is independently selectedfrom the group consisting of hydrogen, hydrocarbyl, substitutedhydrocarbyl, heteroatom-containing hydrocarbyl, and substitutedheteroatom-containing hydrocarbyl; each of R³ through R⁸ is selectedfrom the group consisting of hydrogen, hydrocarbyl, substitutedhydrocarbyl, heteroatom-containing hydrocarbyl, and substitutedheteroatom-containing hydrocarbyl; Z is selected from the groupconsisting of —O, —S and —NR²², wherein R²² is selected from the groupconsisting of hydrocarbyl, substituted hydrocarbyl,heteroatom-containing hydrocarbyl, and substituted heteroatom-containinghydrocarbyl; M is selected from the group consisting of Li, Na,hydrogen, SiR¹²R¹⁴R¹⁵, SnR¹⁶R¹⁷R¹⁸, BR¹⁹R²⁰, MgX′₂ and ZnX″₂, wherein:each of R¹³ through R¹⁸ is independently selected from the groupconsisting of hydrocarbyl, and substituted hydrocarbyl, each of R¹⁹ andR²⁰ is independently selected from the group consisting of hydrogen,hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl,and substituted heteroatom-containing hydrocarbyl, and each of X′ and X″is independently selected from the group consisting of halogens; X is ahalogen; and any two or more of R_(a) and R³ through R⁸ optionallycombine to form a ring.
 26. The method of claim 25, wherein R_(a) is anethylene moiety or phenyl moiety.
 27. The method of claim 25, wherein Mis a trialkyl tin moiety or a zinc halide moiety.
 28. The method ofclaim 26, wherein M is a tributyl tin moiety or a zinc chloride moiety.